CN102811745B - 包含前列腺素e1(pge1)的脂质体,包含它们的制剂及它们的应用 - Google Patents
包含前列腺素e1(pge1)的脂质体,包含它们的制剂及它们的应用 Download PDFInfo
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Abstract
描述了包含与肉碱组合的PGE1和/或PGE1-α-环糊精的单层脂质体，其中在脂质体的外表面上存在有亲水聚合物。
Description
发明领域
本发明涉及药物制剂的领域且特别是包含脂质体的药物制剂领域。
现有技术水平
本发明的目的是制备可用的有效且安全的脂质体，所述脂质体包封了前列腺素E1(PGE1)，用于糖尿病患者的血管疾病的治疗(按照全身施用)及用于皮肤溃疡和糖尿病视网膜病变的局部治疗(按照局部施用)。
当全身施用时，已知前列腺素E1(PGE1)在肺部被迅速代谢，因此明显失去它大部分的效力。
为了克服上述问题，已经研究了磷脂酰胆碱或其它磷脂的脂质体，以确定获得用于与糖尿病相关的病理学病症的治疗的PGE1-α-环糊精复合物的释放的可行性(参见，例如，Toyota T.等：Lipo-PGE1.A newlipid-encapsulation of prostaglandin E1：placebo and prostaglandin E1controlled trails in patients with diabetic neuropathy and leg ulcers.Prostaglandins 1993，46，453-468.)。
在之前的研究(参见Golub M.等：Metabolism of prostaglandins A1 andE1.J.Clin.Invest.1975；56，1404-1410)中，磷脂酰胆碱的脂质体被用作药物载体，以使PGE1能够通过肺过滤器(pulmonary filter)且避免被15-羟基脱氢酶代谢。
考虑到使用PGE1-α-环糊精在治疗糖尿病的血管疾病中及用于皮肤溃疡和糖尿病视网膜病变的局部治疗的重要性，明显需要开发能够克服上述问题的新制剂，保证施用的PGE1的半衰期的有效延长且促进药物在需要部位的释放。
发明概述
描述了包封了结合L-丙酰肉碱的PGE1和/或PGE1-α-环糊精的单层脂质体，所述脂质体的外表面涂有亲水聚合物。
发明详述
由于包含前列腺素E1和L-丙酰基-肉碱的单层脂质体的组合，所述单层脂质体的外表面上存在有亲水性聚合物，本发明允许克服上述问题。
事实上，已经意外地发现，所述聚合物涂层不仅使得脂质体能够更好地粘附到内皮组织的细胞上，而且增强了脂质体在血浆中的稳定性，且因此延长了它的循环时间，由此导致药物的半衰期的增加及递送系统粘合到特定部位的能力的增强。
根据本发明的单层脂质体由包含水溶液的核的磷脂囊泡组成。
组成囊泡的壁的磷脂是天然磷脂或合成磷脂，这是鉴于它们的生物相容性高且无毒性。
适合用于根据本发明的应用的磷脂包括，例如：磷脂酰胆碱(卵磷脂)、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二肉豆蔻酰磷脂酰胆碱(DPMC)、二棕榈酰磷脂酰胆碱(DPPC)、二硬脂酰磷脂酰胆碱(DSPC)、棕榈酰-硬脂酰磷脂酰胆碱、鞘磷脂及类似物。
脂质体还可包含作为稳定剂或表面电荷改性剂的添加剂，比如胆固醇、硫酸胆固醇及类似物。
包含在囊泡中的水溶液由磷酸盐缓冲液或生理溶液组成。
如上所述的脂质体包封了活性组分(它以游离的形式[PGE1]或以包合化合物的形式[PGE1-α-环糊精])和L-丙酰-肉碱，其目的是促进脂质链的β-氧化，增强内皮细胞的代谢。
然后，使脂质体的外表面涂有亲水聚合物，比如聚-L-赖氨酸(PLL)、聚鸟氨酸和纤连蛋白，或其混合物。
优选聚-L赖氨酸，以保证对于培养平板中的细胞的粘附，因为已经证明聚-L赖氨酸使脂质体粘附到内皮细胞上。
用已知的技术，从多层脂质体囊泡(MLV)开始，通过用合适的挤出机使多层脂质体囊泡挤出通过聚碳酸酯过滤器或通过均化，可制备根据本发明的小单层囊泡(SUV)。
因此得到的SUV然后通过逐滴地将脂质体“滴入”到不断搅拌的聚合物溶液中而涂有亲水聚合物。
根据已知的方法，在高于所用的磷脂的转变温度(Tc)的温度下在机械搅拌下通过将所有的组分(磷脂、任何的稳定剂、PEG1和/或PGE1-α-环糊精、肉碱)分散在磷酸盐缓冲液(pH 7.4)，还可制备多层脂质体囊泡(MLV)。通过被挤出通过聚碳酸酯膜或通过均化，用得到的MLV来获得SUV。然后，通过借助渗析消除未包封的活性组分纯化因此得到的SUV。
因此，用于全身应用的制剂由用例如盐水溶液适当地稀释的因此得到的脂质体组成，例如，为了获得适合于例如通过静脉注射在24小时内缓慢输注的全身施用的制剂。
如果需要用于局部应用(例如，用于如前所述的溃疡或视网膜病变的治疗)的制剂，将脂质体分散在适合的聚合物膜中。
所述膜是已知的且用有机聚合物来制备，比如以合适比例的透明质酸钠、羟丙基纤维素(HPMC)、聚乙二醇400(PEG 400)和水，且根据它们的粘弹性性质、厚度和体外生物粘附性，分别用流变仪、测微计和张力计来表征。
然后，用膜来制备用于由例如待应用于损伤或待治疗的表面上的各种尺寸的条(strip)组成的原位应用的药物。它们还可以以隐形眼镜的形式，以直接应用于眼，用于视网膜病变的治疗。
如果需要，还可以冻干制剂且随后在使用它们时重构。
活性组分和肉碱在脂质体中的包封效率(E％)可通过HPLC来测定(显然是在用诸如Triton X-100的合适的膜溶解剂分解脂质体后)。
根据它们的尺寸、多分散指数(PI)和z电势来表征脂质体，同时在透射式电子显微镜(TEM)和偏振光光学显微镜(polarised-light opticalmicroscope)下研究它们的形态学特征和结构特征。
用Franz扩散池来进行体外释放研究。
然后，在体外用内皮细胞来测试涂覆和未涂覆的脂质体，以评估所用的聚合物对囊泡粘附到所述细胞的影响。
还评估PGE1在细胞内的分布。
用涂有亲水聚合物且包含PGE1(以游离和复合物形式)的脂质体来处理细胞。用亲水染料和亲脂染料来“标记”脂质体，以使它们能够被定位在细胞内。在实验的最后，固定细胞且在显微镜下研究，以确定脂质体的内化和它们的位置。
现在参考下面给出的实施例来阐述本发明。
实施例1
在无菌条件下，用无菌原料来制备脂质体。使用磷脂酰胆碱(50mg/ml)、PGE1(游离的或复合的)(60μg/ml)和L-丙酰-肉碱(10mg/ml)的溶液。将组分放置在具有无菌水介质(缓冲液、pH 7.4)的合适的无菌容器中。
在不断的机械搅拌下，维持分散2小时。从而得到多层脂质体(MLV)的均化胶体(囊泡的(vesicular))的分散体。
然后，用具有50nm的孔径的聚碳酸酯过滤器挤出MLV，以得到小单层囊泡(SUV)。
然后，渗析单层脂质体，以除去任何未包封的药物。
然后，将得到的脂质体“逐滴地倾泻”到在对应于(0.01-1％)的浓度下的聚赖氨酸(MW 150,000-300,000)的溶液中且在不断的搅拌下维持2-3小时，以保证(带正电荷的)亲水聚合物和(带负电荷的)脂质体表面的静电相互作用。在脂质体和聚合物之间的相互作用可从表面电荷的变化(z电势变成正的)和从囊泡的尺寸(从60nm-98nm)来识别。
然后，可以冻干得到的脂质体并在室温下保存，且可以用它们来制备用于全身施用的制剂，例如在0.09％盐水溶液中稀释。
可选择地，如果需要制备用于局部应用的制剂，将涂覆或未涂覆的脂质体包含在聚合物膜中，用于药物的局部施用。以合适的比例，用透明质酸钠、羟丙基纤维素(HPMC)、聚乙二醇400(PEG 400)和水来制备膜。
根据它们的粘弹性性质、厚度和生物粘附性，分别用流变仪、测微计和张力计体外地表征膜。再次，用Franz扩散池来进行体外释放研究。
脂质体表征
发现脂质体的平均直径为60nm，同时多分散指数为0.2。
纯化后，包含在脂质体中的PGE 1的数量在30-50μg/ml的范围内，同时肉碱的量在0.05-0.2mg/ml的范围内。
根据它们的尺寸、多分散指数(PI)和z电势，使用Zetasizer Nano(Malvern Instruments，UK)，分别通过光子相关光谱(PCS)(尺寸和PI)和测量恒温控制池中的颗粒的电泳迁移率(z电势)的M3-PALS(光散射相位分析(phase analysis light scattering))来表征脂质体。
Claims (10)
1.单层脂质体，包含与L-肉碱组合的PGE1，其中在所述脂质体的外表面上存在有亲水聚合物，其中所述亲水聚合物是聚-L-赖氨酸。
2.根据权利要求1所述的单层脂质体，包含选自以下的天然或合成的磷脂：卵磷脂、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰甘油、磷脂酰肌醇、二肉豆蔻酰磷脂酰胆碱DPMC、二棕榈酰磷脂酰胆碱DPPC、二硬脂酰磷脂酰胆碱DSPC、棕榈酰-硬脂酰磷脂酰胆碱、鞘磷脂。
3.根据权利要求2所述的单层脂质体，其中所述脂质体还包括作为稳定剂或表面电荷改性剂的添加剂。
4.根据权利要求1所述的单层脂质体，其中所述PGE1是以游离形式或作为包合复合物PGE1-α-环糊精两者的E1前列腺素。
5.用于制备根据权利要求1-4中任一项所述的脂质体的方法，其中所述脂质体通过多层脂质体的均化或挤出通过聚碳酸酯过滤器来得到。
6.用于全身施用的制剂，包含根据权利要求1-4中任一项所述的脂质体。
7.用于局部应用的制剂，包含根据权利要求1-4中任一项所述的脂质体。
8.根据权利要求7所述的制剂，其中所述制剂包含分散在聚合物膜中的根据权利要求1-4中任一项所述的脂质体。
9.根据权利要求8所述的制剂，其中所述聚合物膜用选自以下的有机聚合物来制备：合适比例的透明质酸钠、羟丙基纤维素、聚乙二醇400和水。
10.根据权利要求9所述的制剂，由待应用于损伤或待治疗的表面上的各种尺寸的条组成。
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| ITFI2010A000013A IT1397867B1 (it) | 2010-02-03 | 2010-02-03 | Liposomi contenenti prostaglandina e1 (pge1), formulazioni che li contengono e loro uso |
| IT2010A000013 | 2010-02-03 | ||
| PCT/IB2011/050463 WO2011095938A1 (en) | 2010-02-03 | 2011-02-03 | Liposomes containing prostaglandin e1 (pge1), formulations containing them and their use |
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| ITRM20120036A1 (it) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | Applicazione transdermica di prostaglandina e1 per il trattamento dell¿ischemia oculare. |
| ITFI20120092A1 (it) * | 2012-05-14 | 2013-11-15 | Giovanni Brotzu | Liposomi contenenti prostaglandina e1 (pge1) ed un estrogeno vegetale, formulazioni per uso topico che li contengono e loro uso. |
| HUE037543T2 (hu) * | 2014-05-06 | 2018-09-28 | Fidia Farm Spa | Di-homo-gamma linolénsavat (DGLA) tartalmazó liposzómák, az azokat tartalmazó készítmények és alkalmazásuk |
| CN107049942A (zh) * | 2016-12-30 | 2017-08-18 | 北京普德康利医药科技发展有限公司 | 一种前列地尔注射液 |
| IT201700059875A1 (it) * | 2017-05-31 | 2018-12-01 | Univ Degli Studi Cagliari | Complessi a base di fosfolipidi, fibre idrosolubili e principi attivi antiossidanti di origine naturale, loro preparazione e uso in formulazioni orali |
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| US4311707A (en) * | 1979-02-12 | 1982-01-19 | American Cyanamid Company | Process for topically producing cutaneous vasodilation for the treatment of vasospastic or ischemic conditions |
| US4661105A (en) * | 1981-06-29 | 1987-04-28 | Alza Corporation | Medical bandage for administering vasodilator drug |
| US4846826A (en) * | 1981-07-22 | 1989-07-11 | Alza Corporation | Method for treating ischemic conditions |
| AU617678B2 (en) * | 1987-05-22 | 1991-12-05 | Liposome Company, Inc., The | Prostaglandin-lipid formulations |
| US5811118A (en) * | 1987-05-22 | 1998-09-22 | The Liposome Company, Inc. | Methods of treatment using unilamellar liposomal arachidonic acid metabolite formulations |
| US5853755A (en) * | 1993-07-28 | 1998-12-29 | Pharmaderm Laboratories Ltd. | Biphasic multilamellar lipid vesicles |
| ITRM20010708A1 (it) * | 2001-12-04 | 2003-06-04 | Sigma Tau Ind Farmaceuti | Uso di una alcanoil l-carnitina per il trattamento della disfunzione erettile. |
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Non-Patent Citations (1)
| Title |
|---|
| T.Toyota,et al.Lipo-PGE1,a new lipid-encapsulated preparation of prostaglandin E1:Placebo-and prostaglandin E1-controlled multicenter trials in patients with diabetic neuropathy and leg ulcers.《Prostaglandins》.1993,453-468. * |
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| Publication number | Publication date |
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| CA2787725A1 (en) | 2011-08-11 |
| ITFI20100013A1 (it) | 2011-08-04 |
| CN102811745A (zh) | 2012-12-05 |
| BR112012019344A2 (pt) | 2019-09-24 |
| IT1397867B1 (it) | 2013-02-04 |
| US20130039975A1 (en) | 2013-02-14 |
| WO2011095938A1 (en) | 2011-08-11 |
| DK2531222T3 (da) | 2014-06-23 |
| ES2477233T3 (es) | 2014-07-16 |
| EP2531222A1 (en) | 2012-12-12 |
| EP2531222B1 (en) | 2014-04-02 |
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